Pharmaceutical compositions of pimobendan

ABSTRACT

A composition includes particles of pimobendan with an integral coating of a carrier matrix which serve to ensure a rapid dissolution of the active substance at each pH condition representing the gastrointestinal tract and therefore a reliable absorption, and a method of pimobendan microencapsulation using the spray congealing technology and incorporating the coated particles into oral formulations, for example into tablets.

FIELD OF THE INVENTION

The invention relates to the field of medicine, in particular to thefield of veterinary medicine. The invention relates to improvements inthe oral formulations of the phosphodiestearase inhibitor pimobendanused for the treatment of congestive heart failure originating fromvalvular insufficiency or dilated cardiomyopathy and methods ofproducing the formulations.

BACKGROUND INFORMATION

Pimobendan(4,5-dihydro-6-(2-(4-methoxyphenyl)-1H-benzimidazol-5-yl)-5-methyl-3(2H))-pyridazinone)is a benzimidazole-pyridazone derivative which was described in EP 0 008391 as a substance having cardiotonic, hypotensive and antitromboticactivities.

EP 0 439 030 discloses the low solubility of pimobendan in aqueousenvironment which is still characterized by a highly pH-dependentnature. Depending on the buffer system used, about 100 to 300 mg/literdissolve at a pH between 1 and 3, but at pH 5 only about 1 mg/liter willdissolve in water. In humans, this phenomenon resulted in stronglyfluctuating blood concentrations that levels were often too low. Theseunsatisfactory absorption characteristics were explained by the highpH-dependency of the solubility of pimobendan in aqueous media and byfluctuating pH conditions in the gastrointestinal tract of the testsubjects. According to this patent, the low solubility and high pHdependency of the solubility of pimobendan can be overcome by using anintimate dry admixture of powdered pimobendan and powdered citric acidwherein said admixture is up to about one part by weight of pimobendanper no less than about five parts by weight of citric acid andpharmaceutically active carriers, being filled into capsules orcompressed into tablets for oral administration. The stronglyfluctuating blood concentrations are said to be prevented by the acidmicrosphere, which is caused by the dissolving rate of citric acid,formed around the pimobendan particles. Said microsphere is alwaysacidic and ensures a reliable, practically pH-independent dissolutionand absorption of pimobendan.

WO 2005/084647 relates to a novel solid formulation comprisingpimobendan which is homogeneously dispersed in a polyvalent acidselected from the group consisting of citric acid, acetic acid, maleicacid, tartaric acid or its anhydride, and a flavoring substance.According to said publication, the high quantity of citric acid and theacidic taste of it is not readily accepted by most animals. Thus, theseformulations have to be force-fed to the animals or mixed with foodprior to application. According to WO 2005/084647, these difficultiescan be overcome by using this novel formulation preferably in the formof tablets. Most preferred is a tablet characterized in that the tabletcomprises 1.25 mg, 2.5 mg, 5 mg or 10 mg pimobendan, and furthercomprises citric acid, preferably at an amount of 50 mg/g of the solidformulation, artificial beef flavor and pharmaceutically acceptableexcipients.

WO 2010/055119 discloses a novel formulation, comprising pimobendan andan organic carboxylic acid, wherein the only organic carboxylic acid issuccinic acid, and the weight ratio of succinic acid to pimobendan is atleast 11:1.

WO 2010/010257 relates to the use of a coating composition forapplication to a solid veterinary pharmaceutical composition made frompimobendan by a method of film coating comprising a powder appetizingmaterial, a binder and a solvent.

EP 2 338 493 provides new crystalline forms of pimobendan, thesolubility characteristics of which are such that adding an organic acidor an anhydride thereof is not needed for ensuring a satisfactoryresorption of the substance.

As regards to its biopharmaceutics properties, pimobendan can beclassified in Class IV in the Biopharmaceutics Classification Systems(BSC). This means that it exhibits challenging molecular properties suchas low solubility and low permeability; both of them are consideredrate-limiting steps for absorption. However, the unsatisfactoryabsorption characteristics of pimobendan can be explained primarily bythe high pH-dependency of its solubility in aqueous media and byfluctuating pH conditions in the gastrointestinal tracts of the targetanimals to be treated. It is known that even the pH of the gastricjuices may vary in a relatively wide range, namely between 1 and 5,depending on the presence of food. The fasted gastric pH in dogs wasfound to vary between 0.9 and 2.5, whereas the gastric pH may exhibit a2-3 pH unit elevation in the first postprandial hour. In addition, theintestinal juices are also characterized by fluctuating pH conditionsranging from 3 to 7.5.

According to the state in the art, the unsatisfactory absorption ofpimobendan due to its high pH-dependency of solubility is prevented bysimultaneously administering great amounts of an organic acid in theformulation or using a different crystalline form (polymorph) of the substance.

The objective underlying the present invention is therefore to providean improved pimobendan formulation, which overcomes the problems of theprior art.

SUMMARY OF THE INVENTION

Surprisingly, the inventor has now succeeded in overcoming the highpH-dependency of the solubility of pimobendan and ensuring a verysatisfactory dissolution rate at all pH conditions representing thegastrointestinal tract and therefore a satisfactory absorption, even ifthere are considerable pH fluctuations in the gastrointestinal tract,without using an organic carboxylic acid or modifying the crystallineform of the substance by applying the lipid embedding (lipid coating)approach. The lipid-embedded particles of pimobendan are produced byusing the spray congealing technology, for example as described in U.S.Pat. No. 4,865,851. Spray congealing (also known as spray chilling) isone of the methods used to produce microparticles or more specificallymicrospheres. These are solid, approximately spherical particles withsizes in the micrometer range, in which the drug is evenly distributedwithin the entire volume of the particle. The embedded particles exhibita rapid and substantial dissolution of pimobendan from oral formulationsat each pH representing the gastrointestinal tract of target animalsensuring an adequate absorption of the drug independently from thehighly varying pH conditions. The spray congealing technology elaboratedfor production of the lipid-embedded particles is rapid, easilyscaled-up and low expensive. It is environmentally friendly as nosolvent is required in the formulation and manufacturing process. Usingthe lipid-embedded particles it was possible to formulate palatable oralpimobendan formulations which are rapidly and substantially dissolvingat all pH conditions representing the milieu(s) of the gastrointestinaltract without including any acidic compounds.

In one aspect, the objective of the present invention has surprisinglybeen solved by providing a composition comprising pimobendan inparticulate form coated with a carrier matrix, wherein the carriermatrix consists essentially of one or more pharmaceutically acceptablecarriers selected from the following groups:

a. polyglycolized glycerides,

b. polyethylene glycols (PEGs).

In another aspect, the objective of the present invention hassurprisingly been solved by providing a composition comprisingpimobendan in particulate form coated with a carrier matrix, wherein thecarrier matrix consists essentially of one or more pharmaceuticallyacceptable carriers selected from the following groups:

a. polyglycolized glycerides,

b. polyethylene glycols (PEGs),

and wherein the coating with the carrier matrix serves to ensure a rapidand substantial dissolution of pimobendan irrespective of the pHconditions.

In yet another aspect, the objective of the present invention hassurprisingly been solved by providing a process for the preparation of acomposition as herein disclosed, which comprises

a. dispersing particulate pimobendan in a molten carrier matrix,

b. atomizing the dispersion obtained in step (a), and

c. cooling and collecting the coated particles.

In yet another aspect, the objective of the present invention hassurprisingly been solved by providing a composition comprisingpimobendan in particulate form coated with a carrier matrix obtainableby the processes for the preparation of a composition as disclosedherein.

In yet another aspect, the objective of the present invention hassurprisingly been solved by providing a pharmaceutical composition fororal administration to warm-blooded animals, preferably companionanimals, in particular dogs, comprising a veterinarily effective amountof the composition as described herein, one or more physiologicallyacceptable excipients, and optionally, veterinarily effective amounts ofone or more further active ingredients selected from the groups ofangiotensin enzyme (ACE) inhibitors, aldosterone antagonists and/or loopdiuretics.

By applying the pharmaceutical composition according to the presentinvention, the low solubility and high pH-dependency of solubility ofpimobendan can be overcome without administering simultaneously greatamounts of organic acid or using a different crystalline form(polymorph) of the substance as it is demonstrated by the rapid andsubstantial dissolution of the active compound at each pH representingthe milieu(s) of the gastrointestinal tract of animals. The practicallypH-independent dissolution ensures satisfactory absorption even atfluctuating pH conditions of the treated subjects.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1: Comparative dissolution profiles of tablet formulationscontaining 5 mg pimobendan prepared according to Example 3 of theinvention and available commercially as chewing tablets, respectively inhighly acidic pH region (pH 1.2). Conditions of testing: V=1000 ml,rotation speed=100 rpm, chromatographic conditions: Agilent Infinity1290 UHPLC, RP18, 50×3.0 mm, 1.7 μm column, 27:73 v/v % acetonitrile:phosphate buffer as mobile phase, 0.4 ml/min flow rate, 290 nm detectionwavelength.

FIG. 2: Comparative dissolution profiles of tablet formulationscontaining 5 mg pimobendan prepared according to Example 3 of theinvention and available commercially as chewing tablets, respectively inmoderately acidic pH region (pH 4.5). Conditions of testing are the sameas for FIG. 1.

FIG. 3: Comparative dissolution profiles of tablet formulationscontaining 5 mg pimobendan prepared according to Example 3 of theinvention and available commercially as chewing tablets, respectively inneutral acidic pH region (pH 7.5). Conditions of testing are the same asfor FIG. 1.

DETAILED DESCRIPTION OF THE INVENTION

Before the embodiments of the present invention are described in furtherdetails it shall be noted that as used herein and in the appendedclaims, the singular forms “a”, “an”, and “the” include plural referenceunless the context clearly dictates otherwise.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meanings as commonly understood by one of ordinary skillin the art to which this invention belongs. All given ranges and valuesmay vary by 1 to 5% unless indicated otherwise or known otherwise by theperson skilled in the art, therefore, the term “about” was usuallyomitted from the description and claims. Although any methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of the present invention, the preferred methods,devices, and materials are now described. All publications mentionedherein are incorporated herein by reference for the purpose ofdescribing and disclosing the substances, excipients, carriers, andmethodologies as reported in the publications which might be used inconnection with the invention. Nothing herein is to be construed as anadmission that the invention is not entitled to antedate such disclosureby virtue of prior invention.

In one aspect, the objective of the present invention has surprisinglybeen solved by providing the process for the preparation of acomposition as herein disclosed, which comprises

-   -   a. dispersing particulate pimobendan, preferably with a mean        particle size of less than 20 μm, in a molten carrier matrix,        such as polyglycolized glycerides, preferably stearoyl        macrogol-32 glycerides, more preferably Gelucire 50/13, and/or        polyethylene glycols, preferably with an average molecular        weight of 1.500 to 20.000 g/mol, more preferably with an average        molecular weight of 4.000 to 6.000 g/mol, most preferably PEG        6000, wherein the carrier matrix preferably has a melting point        from 40° C. to 80° C., more preferably from 50° C. to 70° C., by        using conventional dispersion techniques, for example, using a        high shear mixer, to yield a dispersion, preferably a homogenous        suspension;    -   b. atomizing the dispersion obtained in step (a) by using        conventional atomizers, such as rotary atomizers, pressure or        pneumatic nozzles and/or sonic nozzles, preferably fitted in a        standard spray congealing/chilling apparatus, more preferably by        using a two-fluid pressure or pneumatic nozzle atomization        system fitted in a standard spray congealing/chilling apparatus,        using atomizing gas pressures of 1 to 10 bar, preferably 2 to 8        bar and more preferably 3 to 6 bar; and    -   c. cooling and collecting the coated particles by conventional        cooling and collecting techniques, for example, by applying a        stream of cool air or an inert gas, such as dry nitrogen,        preferably at a temperature of 0° to 30° C., more preferably at        a temperature of 3° to 15° C., even more preferably at a        temperature of 5° to 15° C., most preferably at a temperature of        4° to 8° C., to the spray apparatus and collecting the        particles, preferably in a cyclone separator or a bag filter.

According to a further aspect, the objective of the present inventionhas surprisingly been solved by providing a composition comprisingparticles of pimobendan with an integral coating of a carrier matrix,wherein the carrier matrix consists essentially of one or morepharmaceutically acceptable carriers from the groups of polyglycolizedglycerides and polyethylene glycols, and wherein the pimobendan exhibitsfrom the composition or relevant drug forms a rapid and extensive (fastand substantial) dissolution at all pH conditions representing themilieu(s) of the gastrointestinal tract of target animals.

According to a further aspect, the present invention providespharmaceutical compositions for oral administration in companionanimals, particularly in dogs, which comprise lipid-embedded particlesof pimobendan in suitable vehicle.

According to a yet further aspect, the invention provides a method ofensuring a reliable, rapid and substantial dissolution of pimobendan ateach pH condition representing the gastrointestinal tract of targetanimals which comprises coating of pimobendan with a suitable carrierand incorporating the embedded particles into oral formulations, forexample into tablets.

In order to effectively overcome the high pH-dependency of thesolubility of pimobendan and provide coated particles exhibiting rapidand substantial dissolution at all pH conditions representing thegastrointestinal tract of dogs, the mean diameter of the coatedpimobendan particles should preferably be less than 50 μm.

The melting point of the carrier should be sufficiently high to preventmelting of the coated particles in the mouth, but not so high thatpimobendan itself melts and/or becomes chemically degraded during thecoating process. Thus, the carrier or a mixture of carriers used ascarrier matrix in the present invention will have a melting point from40° C. to 80° C. and preferably from 50° C. to 70° C.

Suitable carriers for the coating of pimobendan are selected from thegroups of polyglycolized glycerides and polyethylene glycols.

Polyglycolized glycerides are mixtures of glycerides of fatty acids andesters of polyoxyethylene with fatty acids. In these mixtures, the fattyacids are saturated or unsaturated and the glycerides are mono-, di- ortri-glycerides or mixtures thereof in any proportions. Examples ofsuitable polyglycolized glycerides include but are not limited tolauroyl macrogolglycerides or stearoyl macrogolglycerides.

In a particular group of compositions, the polyglycolized glyceridescontained in the carrier matrix have a hydrophilic-to-lipophilic balancevalue (HLB) of greater than 10. In a further particular group ofcompositions, the polyglycolized glycerides contained in the carriermatrix are dispersible in water. In a further particular group ofcompositions, the polyglycolized glycerides are stearoylmacrogolglycerides. In yet a further particular group of compositions,the polyglycolized glyceride is stearoyl macrogol-32 glycerides (forexample Gelucire 50/13). Stearoyl macrogol-32 glycerides aresemi-solid/solid at room temperature, having a melting point of 50° C.

Polyethylene glycols USP (PEGs), alternatively known as macrogols, arehydrophilic polymers of oxyethylene. PEGs having an average molecularweight greater than 900 g/mol are generally semi-solid or solid atambient temperature. A suitable average molecular weight range for PEGsin the present invention is 1.500 to 20.000 g/mol. Suitable commerciallyavailable products include but are not limited to PEG 1500, PEG 4000 andPEG 6000. In a particular group of compositions, the PEG(s) present inthe carrier matrix have an average molecular weight range of between4.000 and 6.000 g/mol. In a further particular group of formulations ofthis embodiment, this PEG has an average molecular weight of around6.000 g/mol.

According to one embodiment of the present invention, the carrier matrixused for coating of pimobendan consists of one or more pharmaceuticallyacceptable carriers selected from the groups of polyglycolizedglycerides and polyethylene glycols.

In a further embodiment of the invention, the carrier matrix is apolyglycolized glyceride. Conveniently, the polyglycolized glyceride islauroyl macrogolglycerides or stearoyl macrogolglycerides, particularlystearoyl macrogol-32 glycerides.

In yet a further embodiment of the invention, the carrier matrix is apolyethylene glycol, particularly PEG 6000.

In a further embodiment of the invention, the carrier matrix comprises amixture of at least one polyglycolized glyceride and at least onepolyethylene glycol. Conveniently, the polyglycolized glyceride presentin this embodiment is stearoyl macrogol-32 glycerides and suitably thestearoyl macrogol-32 glycerides is present in an amount to make up10-100% by weight of the carrier matrix component of the composition,and preferably represents 20-50% by weight of the carrier matrixcomponent of the composition. Conveniently, the polyethylene glycolpresent in this embodiment has an average molecular weight between 4.000and 6.000 g/mol and suitably the PEG is present in an amount to make up10-100% by weight of the carrier matrix component of the composition,and preferably 30-80% by weight of the carrier matrix component of thecomposition. Preferably, there is only one polyglycolized glyceride andone polyethylene glycol present in this embodiment.

In a particular group of formulations of this embodiment, thispolyglycolized glyceride belongs to the stearoyl macrogol-32 glyceridesand the PEG has an average molecular weight of 6.000 g/mol. Preferably,the stearoyl macrogol-32 glycerides and the polyethylene glycol 6000 areindependently from each other present in amounts to make up 10% byweight to 100% by weight of the carrier matrix component of thecomposition, preferably 20% by weight to 75% by weight of the carriermatrix component of the composition, more preferably 20% by weight to50% by weight of the carrier matrix component of the composition.

The lipid-coated particles according to the invention will contain 1 to80%, preferably 5 to 30%, more preferably 10 to 20% pimobendan on aweight-to-weight (w/w) basis.

The lipid-coated particles of the invention are characterized by amedian (D50) value of particle size distribution of generally less than500 μm, preferably less than 300 μm, more preferably less than 250 μmand even more preferably less than 200 μm. Control of the particle sizeis necessary to ensure that the dissolution of pimobendan from thesubsequently formulated product will be rapid and substantial at all pHconditions representing the gastrointestinal tract of the targetanimals. Coated particles having a D50 value of less than 200 μm arepreferred in this respect. The D50 value represents the median particlesize in a given particle size distribution, i.e. the particle size valuewhich 50% of all particles are smaller than. For instance, a D50 valueof 200 μm means that 50% of all particles have a particle size smallerthan 200 μm.

The lipid-coated particles of the invention may be prepared by atomizinga dispersion of pimobendan in a molten carrier matrix and cooling theparticles hereby obtained and such a process constitutes a furtherfeature of the invention. The dispersion may be prepared by addingparticulate pimobendan to the molten carrier or mixture of carriers oralternatively mixing the ingredients of the dispersion together in thesolid state and melting the carrier matrix. The particulate pimobendancan be dispersed in the molten carrier matrix using conventionaltechniques, for example, using a high shear mixer. Generally, thetemperature of the molten carrier matrix should be 20-40° C. above itsmelting point. In general, the carrier or mixture of carriers used forcoating of pimobendan particles should have a melting point within therange of 40 to 80° C., preferably 50 to 70° C., and the temperature ofthe molten carrier matrix will be 20 to 40° C. above its melting point.Atomizing techniques which may be applied include the use ofconventional atomizers such as rotary atomizers, pressure nozzles andsonic nuzzles. The use of a two-fluid nozzle atomizer fitted in astandard spray congealing/chilling apparatus is particularly convenient.

In the atomization process, the molten dispersion will generally besupplied to the atomizer head at a temperature in the range of 70° C. to100° C., preferably 75° C. to 95° C., more preferably 75° C. to 90° C.,the precise temperature depending on the particular carrier matrix used.The atomizing gas supplied to the nozzle may be air or an inert gas suchas nitrogen. The pressure of the atomizing gas is between 1 and 10 bar,preferably between 2 and 8 bar and more preferably between 3 and 6 bar.The atomizing pressure is desirably controlled in order to produceparticles of the preferred size.

The coated particles may be solidified and collected by conventionaltechniques. The coated particles may conveniently be solidified byapplying a stream of cool air or dry nitrogen to the spray chamber at atemperature between 0° C. to 30° C., preferably 3° C. to 15° C., morepreferably 5° C. to 15° C., most preferably 4° C. to 8° C. Thelipid-coated particles are collected as a free flowing powder usingeither a cyclone separator or a bag filter. The coated particles arespherical in shape and have a D50 value of less than 500 μm, preferablyless than 300 μm, more preferably less than 250 μm, and even morepreferably less than 200 μm.

The lipid-coated particles of the invention may be incorporated into apharmaceutical composition for oral administration, using furtherpharmacologically active ingredients and/or physiologically acceptablecarriers and/or excipients.

The compositions according to the invention may for example includetablets, granules, powders, suspensions, oral pastes and gels. Tabletsincluding chewable tablets represent the particularly preferred dosageform.

Accordingly, the present invention relates in one embodiment to an oralpimobendan formulation, preferably a tablet, comprising

-   -   a veterinarily effective amount of pimobendan as active        substance in the lipid-coated particulate form, and    -   physiologically acceptable excipients.

The amount of pimobendan in the oral formulations is preferably in therange of 0.01% to 10% by weight, more preferably 0.5% to 1.0% by weight,based on the entire formulation.

The oral pimobendan formulations of the present invention may alsocomprise veterinarily effective amounts of further active ingredientswhich may be selected from angiotensin converting enzyme (ACE)inhibitors, aldosterone antagonists and/or loop diuretics. Non-limitingexamples of actives which may be used in combination with thelipid-coated pimobendan particles according to the invention are:benazepril (CAS No. 86541-75-5), spironolactone (CAS No. 52-01-7) and/orfurosemide (CAS No. 54-31-9), all and independently from each other infree form or in the form of a physiologically acceptable salt, whichpreferably is embedded into a (lipid) carrier matrix. That is thefurther active substances may also be added to the oral pimobendanformulations in the form of lipid-embedded particles, produced by usingthe spray congealing technique, i.e. particles coated with a (lipid)carrier matrix. Preferably, the oral pimobendan formulations of thepresent invention also comprise veterinarily effective amounts ofbenazepril, in free form or in the form of a physiologically acceptablesalt, which preferably is embedded into a carrier matrix. The furtheractive substances may be present in the oral formulations of theinvention in the range of 0.01 to 50% by weight, preferably from 0.1 to20% by weight, based on the entire weight of theformulation/composition.

The oral pimobendan compositions may be formulated using conventionalpharmaceutically acceptable excipients. Thus for example tablets may beprepared by using binding agents (e.g. pregelatinised starch, polyvinylpyrrolidine or hydroxypropyl methyl cellulose), fillers (e.g. lactose,microcrystalline cellulose or calcium hydrogen phosphate), lubricants(e.g. magnesium stearate, talc or colloidal silica), disintegrants (e.g.starch or sodium starch glycolate) or wetting agents (e.g. sodium laurylsulphate). The tablet formulations of the present invention, inaddition, contain one or more attractive, physiologically acceptablenatural or synthetic flavorings. Preferred flavoring agents areartificial beef flavor, liver powder and brewer's yeasts. The flavoringagents are present preferably in the tablet formulations of theinvention in the range of 1.0% by weight to 60% by weight, morepreferably from 5.0% by weight to 30% by weight, based on the entireweight of the formulation/composition.

The oral paste or gel formulation of the present invention, may containpharmacologically acceptable excipients, for example thickeners (e.g.xanthan gum, polyvinyl pyrrolidones, polyacrilates such as carbopols,cornstarch, microcrystalline cellulose, hydroxyethyl cellulose, silicondioxide or combinations thereof), humectants (e.g. glycerol),preservatives (e.g. benzyl alcohol, benzoic acid, benzoates orp-hydroxibenzoates, pH-adjusting agents (bases or acids), binders,fillers, surface active or dispersing agents. Said pharmacologicallyacceptable excipients are known to those skilled in the art ofveterinary formulation technology. The oral paste and gel formulationsof the present invention also contain veterinarily acceptable attractiveflavorings. Suitable flavoring agents within the compositions of theinvention are, for example, artificial beef flavor, food extracts suchas desiccated liver or malt extract and honey flavors.

The pharmaceutical compositions of the invention may be preparedaccording to conventional techniques well known in the pharmaceuticalindustry. Thus, for example tablets may be prepared by directcompression of a dry admixture of the lipid-coated pimobendan particleswith excipients and optionally with further active substances or by wetgranulation. Oral paste or gel formulations may be obtained bydispersing the lipid-coated particles of pimobendan and optionallyfurther active ingredients in suitable vehicles.

The compositions for use according to the present invention may, ifdesired, be presented in a pack or dispenser device which may containone or more unit doses. The pack may for example comprise metal orplastic foil, such as blister pack.

The formulations of the present invention are suitable for the treatmentof congestive heart failure originating from valvular insufficiency ordilated cardiomyopathy in companion animals, in particular in dogs.

The efficacy is based on a satisfactory dissolution and subsequentabsorption of the active substance. The dissolution profiles obtainedfrom the tablet formulation according to the present invention and thosefrom commercially available tablets, both of them containing 5 mgpimobendan, were compared at pH 1.2, 4.5 and 7.5 buffers, i.e. at pHconditions representing different parts/milieus of the gastrointestinaltract of companion animals. The dissolved concentrations of pimobendanwere determined by a validated UHPLC method.

The oral formulations according to the present invention exhibit a highpalatability meaning the voluntary acceptance or ingestion of theformulations by warm-blooded animals, for instance companion animals, inparticular by dogs. The acceptance of the oral formulations containinglipid-coated pimobendan particles and suitable further ingredientsaccording to the present invention was tested on dogs.

EXAMPLES

The following examples serve to further illustrate the presentinvention; but the same should not be construed as a limitation of thescope of the invention disclosed herein.

Example 1—Lipid Coating of Pimobendan

Gelucire 50/13 (18.0 kg) was melted in a stainless steel vessel andraised to a temperature of 85° C. Pimobendan (2.0 kg) with a meanparticle size <20 μm was added to the molten lipid. The moltendispersion was mixed with a high shear mixer to give a homogeneoussuspension and pumped to a spray congealing apparatus. The mixture wasatomized using a two-fluid nozzle atomization system at atomizing gaspressures of 3 to 6 bar. The atomized droplets were chilled using airfed into the spray chamber at a temperature of 5 to 10° C. and the solidparticles were collected in a cyclone separator. The lipid-coatedpimobendan comprised spherical particles with a mean particle size of 90μm.

Example 2—Lipid Coating of Pimobendan

Gelucire 50/13 (4.5 kg) and PEG 6000 (13.5 kg) were melted in astainless steel vessel while raising the temperature to 90° C. To thiswas added pimobendan (2 kg) with a particle size of <20 μm. The moltendispersion was subjected to high shear mixing to obtain a homogenoussuspension and this mixture was spray chilled as described in Example 1,to give a lipid-coated product having a similar particle size and shape.For example, three different batches were produced with D50 values of118 μm, 136 μm and 166 μm, respectively.

Example 3—Tablet Formulation

Pimobendan embedded into a carrier matrix comprising Gelucire 50/13 andPEG 6000 was blended with pig liver flavor, yeast powder and furtherexcipients in a rotary blender. The resultant mixture was compressedinto tablets using a suitable tablet press and suitable punches.

Direct Compression Tablets Amount (% w/w) Lipid-coated Pimobendan 6.3Lactose 20.5 Pig liver powder 20.0 Microcrystalline cellulose 19.0Pregelatinised starch 11.2 Sodium starch glycolate 10.0 Yeast powder10.0 Talc 2.0 Magnesium stearate 1.0

Example 4—Tablet Formulation

Pimobendan coated with Gelucire 50/13, furosemide and the excipientswere blended in a rotary mixer, and then the blend was compressed intotablets using a suitable tablet press and suitable punches.

Oral Tablet Amount (% w/w) Lipid-coated Pimobendan 3.1 Furosemide 5.0Lactose 25.0 Microcrystalline cellulose 21.9 Artificial beef flavor 20.0Pregelatinised starch 14.0 Sodium starch glycolate 8.0 Talc 2.0Magnesium stearate 1.0

Example 5—Tablet Formulation

The lipid-embedded particles of pimobendan prepared according to Example2 were blended with lipid-coated benazepril, the particles of which wereembedded into a carrier matrix comprising glycerol distearate, yeastpowder, synthetic liver aroma and further excipients, in a rotaryblender, and then the resultant mixture was compressed into tabletsusing a suitable tablet press.

Direct Compression Tablets Amount (% w/w) Lipid-coated Pimobendan 6.3Lipid-coated Benazepril 12.5 Yeast powder 25.0 Sodium starch glycolate15.0 Microcrystalline cellulose 13.2 Lactose monohydrate 12.5Pregelatinised starch 10.0 Synthetic liver flavor 3.5 Talc 2.0

Example 6—In Vitro Dissolution

The absorption of pimobendan highly depends on the dissolution rate ofthe active substance at varying pH conditions representing thegastrointestinal tract. The dissolution profiles of pimobendan fromtablets prepared according to Example 3 of the present invention andcommercially available chewable tablets, both containing 5 mg activesubstance were compared at different pH conditions representing thegastrointestinal tract. The results are presented in FIGS. 1 to 3. Ascan be seen from these data, the dissolution rate of pimobendan from thetablet formulation prepared according to the present invention was rapidand substantial at each pH tested. At pH 1.2 the speed and rate ofdissolution from the formulation according to the present invention andthe commercially available chewable tablets were practically the same.However, at pH 4.5 and 7.5, the dissolution of the active substance wasfaster and more extensive from the tablet formulation according to theinvention than from the reference product. These results clearlydemonstrate that the tablet formulation prepared according to theinvention ensures a very satisfactory dissolution of pimobendan at allconditions representing the gastrointestinal tract, even if there areconsiderable pH fluctuations in it, without comprising any organiccarboxylic acid which is present in great amounts in the commerciallyavailable product.

Dissolution rate (%) - pH 1.2 Time (min) 0 10 15 20 30 45 Formulationacc. to Example 3 0 86.8 91.0 92.7 94.1 96.2 Commercial formulation 074.9 90.0 93.7 93.8 94.5 Dissolution rate (%) - 4.5 Time (min) 0 10 1520 30 45 Formulation acc. to Example 3 0 88.2 92.3 93.2 93.8 93.8Commercial formulation 0 62.0 77.8 85.7 88.7 88.4 Dissolution rate (%) -pH 7.5 Time (min) 0 10 15 20 30 45 Formulation acc. to Example 3 0 85.089.6 89.8 90.4 90.7 Commercial formulation 0 58.6 71.9 78.4 81.1 81.8

Example 7—In Vitro Dissolution

The dissolution profiles of pimobendan and benazepril from tabletsprepared according to Example 5 and containing 2.5 mg pimobendan and 5mg benazepril were compared to commercially available chewable tabletformulations in pH 1.2, 4.5 and 7.5 buffers. The results obtained fromthe present study demonstrate that the dissolution of pimobendan andbenazepril from the formulation containing both active substances in thelipid-embedded form is slower than from the corresponding commercialformulations containing only one active substance, i.e. eitherpimobendan or benazepril, the dissolution rate of both active compoundsat 45 min of dissolution is higher from the combination than from thecommercial mono formulations at each pH condition representing thegastrointestinal tract of dogs.

Dissolution rate (%) - pH 1.2 Time (min) 10 15 20 30 45 0 Pimo Bena PimoBena Pimo Bena Pimo Bena Pimo Bena Formulation 0 32 33 48 47 62 59 82 7889 88 according to Example 5 Commercial 0 63 — 75 — 83 — 87 — 87 —Pimobendan formulation Commercial 0 — 56 — 71 — 76 — 80 — 84 Benazeprilformulation Dissolution rate (%) - pH 4.5 Time (min) 10 15 20 30 45 0Pimo Bena Pimo Bena Pimo Bena Pimo Bena Pimo Bena Formulation 0 38 24 5537 67 48 82 63 82 69 according to Example 5 Commercial 0 58 — 68 — 72 —74 — 73 — Pimobendan formulation Commercial 0 — 34 — 45 — 53 — 58 — 63Benazepril formulation Dissolution rate (%) - pH 7.5 Time (min) 10 15 2030 45 0 Pimo Bena Pimo Bena Pimo Bena Pimo Bena Pimo Bena Formulation 043 33 59 48 70 60 80 73 81 78 according to Example 5 Commercial 0 51 —60 — 64 — 67 — 67 — Pimobendan formulation Commercial 0 — 54 — 61 — 63 —62 — 60 Benazepril formulation Pimo = pimobendan; Bena = benazepril

Example 8—Palatability (Acceptance) Test

30 male and female dogs of different breeds and age were tested at ashelter environment. The testing person offered to each dog a singledaily dose of the tablet formulation prepared according to Example 3 ofthe invention which was adapted to the body weight of the animal for 3days. In the case of tablet formulations of the present invention, in afirst instance the tablet was offered by hand for 30 seconds. If the dogdid not take the formulation it was offered the dog in his empty bowl.The dog had again 30 seconds to take the formulation. If one of theabovementioned offers lead to the dog willingly eaten the tablet, thiswas evaluated as acceptance or voluntarily uptake of the tablet. If thedog spit out the tablet it was reported as not accepted. A voluntarilyuptake was observed in 82 out of the 90 possible opportunities (i.e.when offered to 30 animals for 3 days). This compares to an acceptancerate of 91.1%.

REFERENCES

-   1. EP 0 008 391-   2. EP 0 439 030-   3. EP 2 338 493-   4. WO 2005/084647-   5. WO 2010/010257-   6. WO 2010/055119

What is claimed is:
 1. A method for the preparation of a composition,the process comprising: dispersing particulate pimobendan in a moltencarrier matrix to form particles coated with the carrier matrix, whereinthe molten carrier matrix comprises one or more pharmaceuticallyacceptable carriers selected from the group consisting of apolyglycolized glyceride, a polyethylene glycol, and combinationsthereof; atomizing the dispersion of coated particles; and cooling andcollecting the coated particles from the atomized dispersion.
 2. Themethod of claim 1, wherein the particulate pimobendan has a meanparticle size of less than 20 μm, the carrier matrix has a melting pointfrom 40° C. to 80° C., and the dispersing is performed in a high shearmixer to obtain a homogenous suspension of the coated particles withinthe carrier matrix.
 3. The method of claim 1, wherein the carrier matrixcomprises a polyglycolized glyceride.
 4. The method of claim 1, whereinthe polyglycolized glyceride comprises a stearoyl macrogol-32 glyceride,a lauroyl macrogolglyceride or a stearoyl macrogolglyceride.
 5. Themethod of claim 1, wherein the polyethylene glycol has an averagemolecular weight of 1,500 to 20,000 g/mol, or an average molecularweight of 4,000 to 6,000 g/mol.
 6. The method of claim 1, wherein thepolyethylene glycol comprises PEG
 6000. 7. The method of claim 1,wherein the atomizing the dispersion of coated particles is performedusing an atomizer selected from the group consisting of a rotaryatomizer, a pressure or pneumatic nozzle, a sonic nozzle, andcombinations thereof.
 8. The method of claim 1, wherein the atomizingthe dispersion of coated particles is performed using a two-fluidpressure or pneumatic nozzle atomization system fitted in a spraycongealing/chilling apparatus and using atomizing gas pressures of 1 to10 bar.
 9. The method of claim 1, wherein the cooling and collecting thecoated particles from the atomized dispersion comprises applying astream of cool air or an inert gas at a temperature of 0° to 30° C. froma spray apparatus to the coated particles within a cyclone separator ora bag filter.
 10. The method of claim 9, wherein the cool air or inertgas is applied at a temperature of 5° to 15° C., or at a temperature of4° to 8° C.
 11. The method of claim 1, further comprising: blending thecooled and collected coated particles with one or more additionalcomponents to form a blended mixture; and compressing the blendedmixture to form a tablet.
 12. The method of claim 11, wherein the one ormore additional components comprises one or more additional activeingredients.
 13. A method for the treatment of congestive heart failurein a warm-blooded animal, the method comprising administering to thewarm-blooded animal a veterinarily effective amount of a pharmaceuticalcomposition comprising pimobendan in particulate form coated with acarrier matrix, the carrier matrix comprising one or morepharmaceutically acceptable carriers selected from the group consistingof a polyglycolized glyceride, a polyethylene glycol, and combinationsthereof.
 14. The method of claim 13, wherein the method of treatment isfor congestive heart failure originating from valvular insufficiency ordilated cardiomyopathy in the warm-blooded animal.
 15. The method ofclaim 13, wherein the warm-blooded animal is a dog.
 16. The method ofclaim 13, wherein the pharmaceutical composition further comprises oneor more further active ingredients embedded in a carrier matrix, whereinthe one or more further active ingredients is selected from the groupconsisting of an angiotensin enzyme (ACE) inhibitor, an aldosteroneantagonist, a loop diuretic, and combinations thereof.
 17. The method ofclaim 16, wherein the one or more further active ingredients is selectedfrom the group consisting of benazepril, spironolactone, furosemide, andcombinations thereof.
 18. The method of claim 13, wherein theadministration is an oral administration and the pharmaceuticalcomposition is in the form of a tablet.
 19. The method of claim 13,wherein pimobendan is provided in the pharmaceutical composition in arange from 0.01% by weight to 10% by weight based on the weight of theentire pharmaceutical composition.
 20. The method of claim 13, whereinpimobendan is provided in the pharmaceutical composition in a range from0.5% by weight to 1.0% by weight based on the weight of the entirepharmaceutical composition.
 21. The method of claim 16, wherein the oneor more further active ingredients are independently from each otherpresent in the pharmaceutical composition in the range of from 0.01% byweight to 50% by weight based on the weight of the entire pharmaceuticalcomposition, or from 0.1% by weight to 20% by weight based on the weightof the entire pharmaceutical composition.
 22. The method of claim 13,characterized by dissolution of pimobendan that is more substantial fromthe relevant drug forms at all pH conditions representing the milieu(s)of the gastrointestinal tract of animals.